Mycobacteria activate γδ T-cell anti-tumour responses via cytokines from type 1 myeloid dendritic cells: a mechanism of action for cancer immunotherapy

• DOI: 10.1007/s00262-011-1121-4
• Publication Date: 2011-10-14T16:01:08Z
• Authors: Daniel W. Fowler; John Copier; Natalie Wilson; Angus G. Dalgleish; Mark D. Bodman-Smith
• Keywords: Cytotoxicity, Immunologic; Cancer Research; Immunology; Receptors, Antigen, T-Cell, gamma-delta; Dendritic Cells; Th1 Cells; Lymphocyte Activation; Vaccines, Attenuated; Mycobacterium; 3. Good health; 03 medical and health sciences; 0302 clinical medicine; Oncology; Antigens, Neoplasm; Neoplasms; BCG Vaccine; Immunology and Allergy; Cytokines; Humans; Original Article; Myeloid Cells; Immunotherapy; Cells, Cultured

Attenuated and heat-killed mycobacteria display demonstrable activity against cancer in the clinic; however, the induced immune response is poorly characterised and potential biomarkers of response ill-defined. We investigated whether three mycobacterial preparations currently used in the clinic (BCG and heat-killed Mycobacterium vaccae and Mycobacterium obuense) can stimulate anti-tumour effector responses in human γδ T-cells. γδ T-cell responses were characterised by measuring cytokine production, expression of granzyme B and cytotoxicity against tumour target cells. Results show that γδ T-cells are activated by these mycobacterial preparations, as indicated by upregulation of activation marker expression and proliferation. Activated γδ T-cells display enhanced effector responses, as shown by upregulated granzyme B expression, production of the T(H)1 cytokines IFN-γ and TNF-α, and enhanced degranulation in response to susceptible and zoledronic acid-treated resistant tumour cells. Moreover, γδ T-cell activation is induced by IL-12, IL-1β and TNF-α from circulating type 1 myeloid dendritic cells (DCs), but not from type 2 myeloid DCs or plasmacytoid DCs. Taken together, we show that BCG, M. vaccae and M. obuense induce γδ T-cell anti-tumour effector responses indirectly via a specific subset of circulating DCs and suggest a mechanism for the potential immunotherapeutic effects of BCG, M. vaccae and M. obuense in cancer.